tbuckley/cabot-search huggingface dataset:
IMMU-46. MONITORING T-CELL DYNAMICS AND CHECKPOINT EXPRESSION IN THE IMMUNE MICROENVIRONMENT OF PEDIATRIC HIGH GRADE BRAIN TUMORS: THE MIMIC PROGRAM
Authors: Joyce Meesters-Ensing, Tiago Carvalheiro, Mariëtte Kranendonk, Kirsten Van Baarsen, Eelco Hoving, Friso Calkoen, Jasper van der Lugt, Stefan Nierkens
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pediatric high grade brain tumors (pHGBT) pose a significant challenge due to limited treatment options and poor prognosis. Understanding the immune landscape, in particular T cell profiles and functionality, is of high interest as numerous immunotherapeutic approaches focus on or utilize T-cells. This study aimed to characterize T-cell phenotypes and their potential for immunotherapeutic interventions in tumor fragments (obtained from cavitron ultrasonic surgical aspiration (CUSA)) and tumor tissue (biopsy), in comparison with peripheral blood, collected from pHGBT patients. METHODS Spectral flow cytometry was employed to characterize the presence of T-cell subsets and their functional phenotype. RESULTS T cells were detected in all materials with similar CD8/CD4 ratios. At diagnosis, T-cells in the tumor microenvironment exhibited significantly increased expression of PD1, LAG3 and TIM3 checkpoint receptors compared to peripheral blood. This difference was more pronounced in biopsy samples compared to CUSA fragments. T-cell composition and phenotype in peripheral blood were similar to healthy adult controls at diagnosis. However, during therapy, the T-cell compartment showed a shift towards a higher CD8/CD4 ratio, accompanied by increased activation markers (CD25, CD69) and checkpoint receptor expression . Notably, CD8+ T-cells in both peripheral blood and tumor microenvironment showed high production of Granzyme B. CONCLUSION Our findings demonstrate that despite the high expression of checkpoint receptors on CD8+ T-cells, these cells retain the capability to produce significant amounts of Granzyme B, indicating their potential for cytotoxic activity. Furthermore, variations in checkpoint receptor expression on T-cells were observed when comparing CUSA fragments to biopsy material. Functional assays will further validate these findings and elucidate the functional status of these cells. Understanding the function of T-cells within the tumor microenvironment is essential for designing novel combination therapies to enhance T-cell cytotoxicity against pHGBT.
CTNI-03. EFFICACY OF WSD0922-FU IN OSIMERTINIB-RESISTANT NSCLC WITH CENTRAL NERVOUS SYSTEM (CNS) METASTASES – UPDATES FROM THE DOSE ESCALATION COHORT OF A FIRST-IN-HUMAN PHASE 1 CLINICAL TRIAL (MC1914)
Authors: Sani H Kizilbash, Kurt Jaeckle, Maciej Mrugala, Jacob Allred, Stephanie Safgren, Renee McGovern, Adam Remick, Joel Reid, Anita Lammers, Wei Zhong, Konstantinos Leventakos, Aaron Mansfield, Mohamed Shanshal, Wen Ma, Joon Uhm, Jian Campian, Michael Ruff, Ugur Sener, Evanthia Galanis, Terry Burns, Ian Parney, Aditya Raghunathan, Rachael Vaubel, Mark Jentoft, Anja Roden, Caterina Giannini, Jann Sarkaria, Alex Adjei
Journal: Neuro-Oncology (2023)

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR aberrant HGA were enrolled and treated across six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles) to determine the maximum tolerated dose (MTD). 25 patients (17 HGA, 8 NSCLC) were enrolled (median age = 57 years; 24% female; 36% ECOG 0). All patients with HGA received prior radiation and temozolomide. All patients with NSCLC had previous disease progression on EGFR inhibitor therapy (prior osimertinib 88%). The median duration of WSD0922-Fu exposure among all patients was 55 days (range 3 to &amp;gt;279 days) [NSCLC median = 131 days; HGA median = 51 days]. Common treatment-related adverse events are comparable to other EGFR inhibitors (fatigue, acneiform rash, diarrhea, nausea, pruritis). At Cycle 1 Day 15 for patients treated at MTD (160 mg twice daily), the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Among patients with NSCLC treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses. Intracranial and extracranial efficacy was concordant. Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Expansion cohorts are in progress to optimize WSD0922-Fu dose and schedule for future phase 2 development.
EPCO-54. GENETIC PROFILE OF SKULL BASE CHONDROSARCOMAS AND RESPONSE TO TREATMENT IN PATIENTS WITH IDH1 MUTATED TUMORS
Authors: Jessica Eaton, Carolina Da Silva Parada, Oscar Parrish, Mallory Tucker, Tina Zhao, Jennifer Delegard, Eric Lassiter, Jacob Ruzevick, Lee Cranmer, Manuel Ferreira
Journal: Neuro-Oncology (2023)

Abstract Chondrosarcomas are uncommon tumors, with an incidence of 0.1-0.3 cases per 100,000 people. Current treatment consists of maximal safe surgical resection. The addition of adjuvant radiation reduces 5-year mortality by about 50%, but recurrence rates at 5 years are still over 30%. Targeted treatment options are needed to improve outcomes for patients with these tumors. IDH catalyzes the oxidative carboxylation of isocitrate to produce a-ketoglutarate. IDH1 mutations been identified across multiple cancers, included gliomas, AML, cholangiocarcinomas, and chondrosarcomas. These mutations are thought to impair cell differentiation and lead to tumorigenesis. OBJECTIVES: We present 2 cases of IDH1 mutant skull base chondrosarcomas that were treated with an IDH inhibitor. Both patients had radiographic involution of their tumors with no progression 2 years later. We describe the genetic profile of chondrosarcomas, elucidate associations between tumor mutations and clinical course, and investigate the mechanism of treatment response. METHODS: We performed a retrospective cohort analysis of 38 patients with skull base chondrosarcomas. Cox proportional hazards models were performed. Whole exome sequencing (WES) was performed on tumor samples, including multiple samples taken at various time points during the clinical course in 3 patients. RESULTS: A total of 38 patients with skullbase chondrosarcomas underwent surgery between 2000 and 2020. Mean follow-up time was 83.3 ± 107.7 months. Mean progression free survival time was 54.4 ± 71.5 months. Mortality was 15.8%. WES was available for 29 patients. Of these, 22 patients had IDH1 mutations (75.9%). Of these 22, the most common amino acid change was at the R132C position (45.5%). There was a trend towards increased mortality in patients that were IDH1 wildtype (42.8%) vs IDH1 mutant (13.6%). CONCLUSION: While IDH1 mutations are possible therapeutic targets with exciting preliminary responses, treatment response is likely complex and dependent on multiple mutations. Further analyses and validation studies are underway.
NCMP-05. INTRACTABLE HEADACHE IN NEWLY DIAGNOSED AML WITH MIGRAINES AND CHIARI MALFORMATION- UNVEILING A COMPLEX SYMPTOM
Authors: Hannah Austin, Laveena Singla
Journal: Neuro-Oncology (2023)

Abstract Acute Myeloid Leukemia (AML) involvement in central nervous system (CNS) is poorly understood in pathophysiology, with reported incidence rates ranging from 1-33% of patients with relapsed AML. CNS involvement is uncommon in the early stages of AML. FLT3-ITD, chromosome 11 abnormalities, and inv(16) cytogenetics are known to have more potential to invade the CNS. A 28-year-old woman with recently diagnosed AML (FLT D835 mutation with deletion in the long arm of chromosome 11) and migraines was admitted for HIDAC consolidation #3. On day two, she started experiencing headaches in the bifrontal and bitemporal regions associated with photophobia, phonophobia, and nausea. Treatment for status migrainous provided little relief. MRI brain showed progression of Chiari malformation (CM) with tonsillar herniation from 16 to 19 mm, which precluded a lumbar puncture. On day 4, she was noted to have grade III papilledema and bilateral cranial nerve IV palsy with non-enhancing patchy increased FLAIR signal in dorsal pons, bilateral cerebral and middle cerebellar peduncles, without diffuse restriction on imaging. The patient underwent sub-occipital craniotomy and C1 laminectomy for decompression for chiari. On day 5, she developed cranial nerve palsies involving nerves VII, IV, and XII. Lumbar puncture (LP) performed after decompression demonstrated elevated opening pressure and 98% abnormal myeloid blast population, confirming CNS involvement of AML. 4 days before starting intrathecal chemotherapy, the patient was found to be in asystole (unclear etiology). This case highlights the range of differential diagnoses for headaches in a patient with multiple comorbidities, including obesity, migraine, Chiari malformation with tonsillar herniation, and cancer. It underscores the necessity for proactive screening of CNS invasion in AML patients with high-risk mutations and neurological symptoms. Moreover, it emphasizes the need to consider CNS involvement in AML patients with headaches, even if standard imaging does not show typical signs of leptomeningeal spread.
DISP-12. BRAIN CANCER CANADA FUNDS CRITICALLY NEEDED RESEARCH AND ADVOCATES FOR PATIENTS, WITH THE AIM TO IMPROVE OUTCOMES FOR CANADIANS DIAGNOSED WITH PRIMARY MALIGNANT BRAIN TUMOURS
Authors: Jessica Soares, Anita Angelini, Ali Ladak, Kaviya Devan, Lia Loebenberg, Elvin de Arujo, Jason Power, Russell Leong, Shamini Ayyadhury, Yung Hoang, Marc Peeters, Angela Scalisi, Brain Cancer Canada
Journal: Neuro-Oncology (2023)

Abstract Brain Cancer Canada (BCC) is a national, volunteer-driven charity supporting paediatric and adult primary malignant brain tumour research and patient advocacy. To achieve these goals BCC 1) awards grants to Canadian doctors and scientists advancing brain cancer research, and 2) advocates for equitable pharmacare for brain cancer patients. BCC is committed to funding innovative research projects, with the aim to improve treatment options for patients. Led by its Scientific Advisory Committee, submissions are reviewed, screened, and undergo a systematic evaluation by the panel. Recommendations on successful proposals are provided to the board for approval. This May, the charity awarded 5 research grants, totaling $380,000 CAD. These projects include supporting the acquisition of a next-generation DNA Sequencer, advancing FET-PET/MRI imaging, pioneering a novel approach to combat Diffuse Intrinsic Pontine Glioma (DIPG), developing a novel dual-hit therapeutic approach for glioblastoma, and other projects focusing on precision medicine. BCC has taken a deliberate and firm stand in highlighting the drug coverage disparities that exist for patients afflicted with brain cancer BCC’s Pharmacare Advocacy Committee has found that disparities exist owing to the lack of a national drug program, and a patchwork of alternative schemes varying by province/territory. These findings are well documented by others. For example, our research shows that temozolomide (TMZ), the global standard of care for treating gliomas, is not covered in 4 provinces. Our pharmacare research on TMZ and 5 other drugs further confirm the disparity in coverage that hinders patient welfare and imposes a confusing and detrimental strain on the healthcare system. With, the dependence on take-home medication increasing, it is critical we take immediate action in supporting this marginalized group. With the support of The Society for Neuro-Oncology, Brain Cancer Canada will be better positioned to reach its goals and support people affected by primary malignant brain tumours.
QOL-28. THE LIVED EXPERIENCE OF PATIENTS WITH CHORDOMA – A RETROSPECTIVE CASE SERIES
Authors: Emmaline Mauritson, Minhdan Nguyen, Judy Truong, Jared Chow, Naveed Wagle, Jose Carrillo, Santosh Kesari, Tiffany Juarez, Garni Barkhoudarian, Daniel Kelly, Gregory Lekovic, Akanksha Sharma
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Chordoma is a rare malignant tumor arising from the skull base or spine with limited treatment options and poor prognosis. Patients with chordoma experience significant physical and emotional symptoms deleterious to quality of life (QOL). Current literature detailing the experiences of patients with chordoma, including end of life, is limited. Each patient’s course differs depending on tumor location, lesion size, metastatic nature of disease, and treatments. We sought to better understand the lived journey of the chordoma patients seen in our center. METHODS This was a retrospective chart review that evaluated a cohort of chordoma patients seen at our center from March 2017 to May 2023. RESULTS/ CONCLUSION A total of 18 patients were included. Average patient age at diagnosis was 53.3 years old (range: 23 to 87 years). Majority were female (67%) and 78% were White/Caucasian. Clival tumors were most common (55%), followed by spine (sacral (28%) and cervical (17%)). Nearly all tumors were recurrent (94%), almost half were metastatic (44%). All patients underwent tumor resection; the average number of surgeries underwent per patient was 2.7. Fifteen patients received radiation (83%) and sixteen patients participated in at least one clinical trial (88%). The average Karnofsky Performance Scale (KPS) at the initial outpatient visit was 80, which decreased to 72.2 by last outpatient visit. Most reported symptoms included emotional distress (78%), neuropathic pain (72%), muscular and bone pain (56%), vision changes (44%), dysphagia (39%), and headaches (39%). The average survival from diagnosis was 3.7 years (range: 2 to 23 years). Eight patients (45%) have passed, 5 of whom were enrolled on hospice at the time of death. Causes of death included seizures (1), respiratory failure due to tumor progression (3), bowel ischemia (1), medical aid in dying (1) and failure to thrive (1).
EPID-07. DISTANT PROGRESSION TO THE POSTERIOR FOSSA IN SUPRATENTORIAL GLIOBLASTOMA: A REPORT OF THREE CASES DURING TUMOR TREATING FIELDS THERAPY
Authors: Juri Kiyokawa, Kaoru Tamura, Kazuhide Shimizu, Tetsuo Ota, Shogo Imae, Mai Sakashita, Shinji Yamamoto, Taketoshi Maehara
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Distant progression of supratentorial glioblastoma (GBM) to the posterior fossa is rare. We report three cases in which such distant progression was observed during Tumor Treating Fields (TTFields) therapy. CASES: All three cases involved solitary supratentorial tumors. Biopsy was performed in case 1 (61-year-old male) and partial resection in cases 2 (69-year-old female) and 3 (73-year-old male). The diagnosis was IDH-wildtype GBM in all three cases. TTFields therapy was performed following chemoradiotherapy. In case 1, distant progression was observed in the dorsal side of the medulla oblongata at 7 postoperative months and in the left cerebellum at 23 postoperative months. The patient died 5 months later. In case 2, distant progression was evident in the pons at 41 postoperative months and the patient died 3 months later. In case 3, distant progression was observed in the cerebellum at 5 postoperative months and the patient died 3 months later. Autopsy was performed in case 1 and revealed multiple separate GBM lesions in the supra- and infratentorial space. Although there was histological heterogeneity within lesions, there was no clear histological difference between supra- and infratentorial lesions. DISCUSSION In the EF-14 trial, although there were no cases of GBM progression to the posterior fossa in the control group who did not receive TTFields therapy (0/122 cases), such progression occurred in 3.6% (11/306) of cases in the TTFields-treated group (p&amp;lt; 0.001). Even though TTFields therapy affords good local control of GBM, distant progression might occur in the posterior fossa, where the electric field effect is poor. Further accumulation and analysis of such cases is warranted.
ANGI-07. GLIOBLASTOMA WITH BONY METASTATIC DISEASE IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1: A CASE REPORT
Authors: Trusha Shah, Troy Hutchens, Jonathan Yang, Jerome Graber
Journal: Neuro-Oncology (2023)

Abstract Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor predisposition syndrome causing diffuse neurofibromas, plexiform neurofibromas, and in a minority of patients malignant peripheral nerve sheath tumors (MPNST) and gliomas. Gliomas from NF1 typically present early in life and can be grade 1-4, with higher grades less frequent. Malignant gliomas associated with NF1 have a different molecular landscape compared to sporadic gliomas. Extracranial spread of gliomas is extremely rare for reasons unknown, but renal transplants from gliomas patients have resulted in clonal gliomas in organ recipients. We present here the first reported case of extracranial metastases of GBM to bone in a 21 year old male with NF1. At the age of 18, he was diagnosed with a high-grade astrocytoma consistent with GBM (IDH wildtype, MGMT unmethylated). This was 2 years following a diagnosis of a right neck plexiform neurofibroma. His GBM was initially treated with six cycles of temozolomide. Following temozolomide he underwent another resection (1.5 years after initial surgery) due to tumor recurrence. Resection was followed by proton radiation therapy and selumetinib, a MEK inhibitor approved for treatment of plexiform neurofibromas in NF1. The selumetinib did reduce his plexiform neurofibroma, but did not have an apparent effect on his GBM. Selumetinib was stopped five months after initiation due to increased tumor burden and he began lomustine, followed by bevacizumab and etoposide at next recurrence. About 2.5 years after his initial GBM diagnosis, he had low back pain and imaging showed multiple sites of bony metastases. Pathology confirmed extracranial spread of GBM.
Effect of Dietary Sodium on Blood Pressure
Authors: Deepak K. Gupta, Cora E. Lewis, Krista A. Varady, Yan Ru Su, Meena S. Madhur, Daniel T. Lackland, Jared P. Reis, Thomas J. Wang, Donald M. Lloyd-Jones, Norrina B. Allen
Journal: JAMA (2023)

Dietary sodium recommendations are debated partly due to variable blood pressure (BP) response to sodium intake. Furthermore, the BP effect of dietary sodium among individuals taking antihypertensive medications is understudied.
CTNI-25. A PHASE 0/1B STUDY OF AZD1390 PLUS RADIOTHERAPY IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Nader Sanai, Siddhi Desai, Tigran Margaryan, Costanza LoCascio, Mackenna Elliott, Jennifer Molloy, Jocelyn Harmon, Amy Hong, Ernesto Luna Melendez, John Wanebo, Kelly Braun, William Kennedy, Michael Garcia, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Shwetal Mehta
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND ATM inhibition has been hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair, and a Phase 1 trial of this combination in patients with GBM is ongoing (NCT03423628). To test this hypothesis, this phase 0/1b study aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, an ATM inhibitor with BBB penetration, in combination with ex vivo radiation in patients with GBM (NCT05182905). METHODS Recurrent GBM patients received 3 days of AZD1390 prior to planned resection at 2-4, 4-6 or 23-25 hours following the final dose. Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase. ATM inhibition was assessed via ex vivo radiation and quantification of pRAD50 levels compared to non-radiated control. Patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen. RESULTS In 17 patients treated to date, AZD1390 was consistently measured in the Gd-non-enhancing tumor region. All patients (n = 17) exceeded the PK threshold to qualify for the expansion phase of the study. With 5Gy ex-vivo radiation of surgical specimen, pRAD50 expression was significantly suppressed in AZD1390 treated patients compared to untreated controls (geomean 1.8% vs 29.1%, average 94% reduction, p &amp;lt; 0.01). Median 6-month progression-free survival has not been reached at a median clinical follow-up of 4.3 months. CONCLUSION AZD1390 is well-tolerated in recurrent GBM patients, achieving pharmacologically relevant concentrations in non-enhancing tumor tissue, and substantially suppressing induction of pRAD50 levels ex vivo post-radiation. This is the first pharmacodynamic evidence that AZD1390 may be a potent radio-potentiator in patients with GBM.
IMMU-47. IMMUNOGENIC AND IMMUNOSUPPRESSIVE ASPECTS OF HSV-TK/GCV-MEDIATED SUICIDE GENE THERAPY IN GLIOMA CELLS
Authors: Jubayer Hossain, Abdul Latif, Romi Chaudhuri, Ege Solel, Lars Ystaas, Rolf Bjerkvig, Hrvoje Miletic
Journal: Neuro-Oncology (2023)

Abstract Suicide Gene therapy (SGT) has been regarded as a promising experimental treatment modality for high-grade gliomas for several decades. However, large-scale clinical trials have failed so far. One hypothesis behind this failure is that, even though SGT directly kills the bulk of the tumor cells, it fails to activate an efficient anti-tumor immune response. Indeed, despite extensive research on SGT, the mechanism of cell death caused by SGT and its immunogenic significance are largely unknown. The most prominent form of SGT— HSV-TK/GCV— for example, is known to kill tumor cells mostly by apoptosis. The immunogenicity of apoptosis in general is controversial and not yet fully explored, especially in the context of SGT. We studied the immunogenic nature of cell death caused by HSV-TK/GCV with two widely used mouse glioma models. To exclude the potential influence of viral vectors on the immune system, we used genetically engineered tumor cells that expresses HSV-TK gene. After orthotopic tumor modelling and SGT with HSV-TK/VGCV, we analyzed the change in immune landscape by using ELISPOT, IHC, FACS and Hyperion in both models. Firstly, we observed that the efficacy of SGT is entirely different in the two glioma models. While in one model tumor growth is only decreased, SGT is curative in the second model. In the non-responding model, an immunosuppressive tumor microenvironment after SGT is observed. Further investigation of the responding model shows that the successful cure is dependent on the availability of an active immune system. We have also identified that the resultant anti-tumor immunity following SGT in this model is mounted by T cells. In conclusion, our data suggest that the immunogenic nature of SGT shows intertumoral heterogeneity and warrants more research to identify the inherent determining factors and mechanisms thereof.